Hruby V J, Agnes R S
Department of Chemistry, University of Arizona, Tucson, Arizona 85721, USA.
Biopolymers. 1999;51(6):391-410. doi: 10.1002/(SICI)1097-0282(1999)51:6<391::AID-BIP3>3.0.CO;2-X.
The discovery of endogenous opioid peptides 25 years ago opened up a new chapter in efforts to understand the origins and control of pain, its relationships to other biological functions, including inflammatory and other immune responses, and the relationships of opioid peptides and their receptors to a variety of undesirable or toxic side effects often associated with the nonpeptide opiates such as morphine including addiction, constipation, a variety of neural toxicities, tolerance, and respiratory depression. For these investigations the need for potent and highly receptor selective agonists and antagonists has been crucial since they in principle allow one to distinguish unequivocally the roles of the different opioid receptors (mu, delta, and kappa) in the various biological and pathological roles of the opioid peptides and their receptors. Conformational and topographical constraint of the linear natural endogenous opioid peptides has played a major role in developing peptide ligands with high selectivity for mu, delta, and kappa receptors, and in understanding the conformational, topographical, and stereoelectronic structural requirements of the opioid peptides for their interactions with opioid receptors. In turn, this had led to insights into the three-dimensional pharmacophore for opioid receptors. In this article we review and discuss some of the developments that have led to potent, selective, and stable peptide and peptidomimetic ligands that are highly potent and selective, and that have delta agonist, mu antagonist, and kappa agonist biological activities (other authors in this issue will discuss the development of other types of activities and selectivities). These have led to ligands that provide unique insight into opioid pharmacophores and the critical roles opioid ligands and receptor scan play in pain, addiction, and other human maladies.
25年前内源性阿片肽的发现为理解疼痛的起源与控制、其与包括炎症及其他免疫反应在内的其他生物学功能的关系，以及阿片肽及其受体与多种通常与非肽类阿片（如吗啡）相关的不良或毒性副作用（包括成瘾、便秘、多种神经毒性、耐受性及呼吸抑制）之间的关系开启了新篇章。对于这些研究而言，强效且高度受体选择性的激动剂和拮抗剂至关重要，因为原则上它们能让人明确区分不同阿片受体（μ、δ和κ）在阿片肽及其受体的各种生物学和病理作用中的角色。线性天然内源性阿片肽的构象和拓扑限制在开发对μ、δ和κ受体具有高选择性的肽配体以及理解阿片肽与阿片受体相互作用的构象、拓扑和立体电子结构要求方面发挥了主要作用。反过来，这又带来了对阿片受体三维药效团的深入了解。在本文中，我们回顾并讨论了一些相关进展，这些进展促成了强效、选择性高且稳定的肽和拟肽配体的出现，它们具有高效力和选择性，且具有δ激动剂、μ拮抗剂和κ激动剂的生物学活性（本期其他作者将讨论其他类型活性和选择性的发展情况）。这些进展带来的配体为阿片药效团以及阿片配体和受体在疼痛、成瘾及其他人类疾病中所起的关键作用提供了独特的见解。
